Compositions of particulate coformulation

ABSTRACT

Embodiments of the invention provide a composition of a particulate coformulation which includes particles containing an active substance and an additive, wherein each particle contains a relative additive concentration increasing radially outwards from a particle center to a particle surface along a finite gradient. In one example, the particle surface is an additive-rich surface without a distinct physical boundary between the particle center and the particle surface. The relative additive concentration may have a continuous rate of change across the finite gradient. In some examples, an active substance:additive ratio of the particle surface is sufficiently low to form a protective surface layer around the active substance. Generally, the particle surface is free of the active substance.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.14/841,325, filed Aug. 31, 2015, which is a continuation of U.S. patentapplication Ser. No. 11/458,008, filed Jul. 17, 2006, now U.S. Pat. No.9,120,031, which is a continuation of U.S. patent application Ser. No.10/004,522, filed Nov. 1, 2001, now U.S. Pat. No. 7,115,280, whichclaims priority to GB 0027353.3, filed Nov. 9, 2000, all of which areincorporated by reference herewith in their entireties.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to methods for preparing particles of an activesubstance which have a layer of an additive, such as a taste maskingadditive, at the particle surfaces. The invention also relates to theparticulate products of such methods.

Description of the Related Art

There are a number of reasons why a particulate active substance (suchas a drug) might need a protective barrier at the particle surfaces. Theactive substance may be physically or chemically unstable, orincompatible with another substance with which it needs to beformulated. It may need protection against, for example, moisture,light, oxygen or other chemicals. A surface coating may alternatively beneeded to delay release of the active substance for a desired timeperiod or until it reaches an appropriate site, or to target itsdelivery to such a site. Drugs intended for oral administration may needcoatings to mask their flavor and render them more palatable topatients.

To protect an active substance in this way, a protective additive needsto be coated onto the external surfaces of the active particles. Severalmethods are known for applying such coatings. Traditional pan orfluidized bed techniques apply a fluid coating directly to solid activeparticles. Alternatively, a thin film layer of a coating material may bedeposited onto particle surfaces by adding the particles to a solutionof the coating material and then removing the solvent, for instance byevaporation, spray drying or freeze drying. Plasticizers, such aspolyethylene glycol (PEG), may be added to the solution to enhancecoating flexibility and surface adhesion. This technique is widely usedin the pharmaceutical industry to coat solid drug dosage forms such astablets, granules and powders.

With changing trends in drug delivery, there is a growing need fordirect coating of drug particles, especially fine particles. Traditionalcoating methods, as described above, involve several stages such ascrystallizing, harvesting, drying, milling and sieving of the drug toobtain particles of the desired size range, and a subsequent, separate,coating step. This increases the risks of product loss andcontamination.

The coating of microfine particles, for instance in the range 0.5-100μm, has often proved particularly problematic due to the large surfacearea of the particles and the non-uniform, often incomplete, coatingsachieved using traditional pan or fluidized bed coating techniques.Problems can be particularly acute if the particles are irregular inshape. If the material to be coated is water soluble, organic solventsare needed for the coating solution, which can lead to toxicity,flammability and/or environmental problems. The coatings achieved canoften cause problems such as increased particle aggregation andincreased residual solvent levels, which in turn can have detrimentaleffects on downstream processing.

In the particular case of taste masking coatings, the need for acontinuous and uniform coating layer is particularly great, since anydiscontinuity in the coating, allowing release of even the smallestamount of a poor tasting active substance, is readily detectable. Thus,the above described problems with prior art coating techniques assumeeven greater significance in the case of taste masking.

Recent developments in the formation of particulate active substancesinclude processes using supercritical or near-critical fluids asanti-solvents to precipitate the active substance from solution orsuspension. One such technique is known as SEDS™ (“Solution EnhancedDispersion by Supercritical fluids”), which is described in WO-95/01221and, in various modified forms, in WO-96/00610, WO-98/36825,WO-99/44733, WO-99/59710, WO-01/03821 and WO-01/15664, which are herebyincorporated in their entirety by reference. The literature on SEDS™refers to the possibility of coating fine particles, starting with asuspension of the particles in a solution of the coating material (seein particular WO-96/00610, page 20 line 28-page 21 line 2, alsoWO-95/01221 Example 5).

Distinct from the coating of particulate actives, it is also known tomix active substances such as drugs with excipients (typically polymers)which serve as carriers, fillers and/or solubility modifiers. For thispurpose the active substance and excipient are ideally coformulated toyield an intimate and homogeneous mixture of the two. Known techniquesinclude co-precipitation of both the active and the excipient from asolvent system containing both. The SEDS™ process may also be used tocoformulate in this way, as described for instance in WO-95/01221(Examples 10 and 16), WO-01/03821 (Examples 1-4) and WO-01/15664.

The products of coformulation processes are generally intimate mixturesof the species precipitated, for instance a solid dispersion of a drugwithin a polymer matrix. This is particularly the case for the productsof a very rapid particle formation process such as SEDS™ (see the aboveliterature). Indeed, because prior art coformulations have for the mostpart been motivated by the need to modify the dissolution rate of anactive substance, they have concentrated (as in WO-01/15664) onobtaining truly homogeneous mixtures of the active and excipient(s),with the active preferably in its more soluble amorphous, as opposed tocrystalline, state.

While such a high degree of mixing is desirable for many products, it isclearly not appropriate where the additive is a surface protector ortaste masking agent, since it leaves at least some of the activesubstance exposed at the particle surfaces, while “tying up” asignificant proportion of the additive within the particle core. In thecase of an unpleasant-tasting drug, even very tiny amounts at theparticle surfaces can be sufficient to stimulate the taste buds, despitethe additional presence of a taste masking agent.

Where such prior art formulations failed to achieve a completelyhomogeneous dispersion of the active in the excipient, for instance athigher active loadings, SEM analysis suggested that they containeddomains of purely crystalline, excipient-free active substance. Thesedomains would be expected to be surrounded by a second phase containinga homogeneous mixture of the remaining active and the excipient. Thistoo would be highly undesirable for taste-masked or otherwisesurface-protected systems; at least some of the active would still bepresent at the particle surfaces. For this reason, active/excipientcoformulation has tended to be used for systems containing lower activeloadings, in order to achieve intimate homogeneous mixtures of theactive (preferably in its amorphous phase) and the excipient.Alternative techniques, using physically distinct active and excipientphases, have been used to achieve coating of actives, especially atrelatively high active:excipient ratios.

Thus coformulation, in particular via SEDS™ as in WO-01/15664, has notpreviously been used to coat active substances with protective agentssuch as taste maskers.

SUMMARY OF THE INVENTION

It has now surprisingly been found, however, that the SEDS™ process canbe used to prepare a particulate coformulation of an active substanceand an additive, generally a protective additive, in which the activesubstance is sufficiently protected, at the particle surfaces, for theprocess to be of use in preparing taste masked or otherwisesurface-protected drugs. The process can generate particles in which theactive substance:additive concentration ratio varies across theirradius, the surface having a sufficiently high additive concentration to“protect” (which includes masking) the active substance, but the core ofthe particle containing a significantly higher concentration of theactive. Thus, although the particles are not strictly “coated”, i.e.,they generally possess no distinct physical boundary between a core anda coating layer, nevertheless they can behave as though coated.

In this way, a SEDS™ process can provide an extremely advantageousmethod for “coating” and protecting active substances. The SEDS™process, as discussed in WO-95/01221 and the other documents listedabove, can bring with it a number of general advantages, such asenvironmental friendliness, versatility and an extremely high degree ofcontrol over the physicochemical properties (particle size andmorphology, for example) of the product. It also allows the single-stepproduction of multi-component products.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-9 are scanning electron microscope (SEM) photographs of some ofthe products and starting materials for Examples A1 to A10 below;

FIGS. 10-12 are X-ray diffraction (XRD) patterns for pure quininesulphate and the products of Examples A6 and A8 respectively;

FIGS. 13-19 are SEM photographs of some of the products and startingmaterials for Examples B1 to B3, C1 and C2 below;

FIGS. 20-21 are XRD patterns for pure sodium chloride and the product ofExample C1 respectively; and

FIGS. 22A-22B show the results of a confocal Raman spectroscopy analysisof the constitution of a product according to the invention.

DETAILED DESCRIPTION

According to a first aspect of the an embodiment of the invention, thereis therefore provided a method for preparing particles of an activesubstance having a layer of an additive at the particle surfaces, themethod involving dissolving both the active substance and the additivein a vehicle to form a target solution, and contacting the targetsolution with an anti-solvent fluid using a SEDS™ particle formationprocess, to cause the active substance and additive to co-precipitate.

In the following description, unless otherwise stated, references to thecrystallinity, morphology, particle growth rate, solubility andmiscibility of a material refer to the relevant properties under theoperating conditions (for example, pressure, temperature, nature ofreagents) used for the particle formation step.

By “active substance” is meant a substance capable of performing someuseful function in an end product, such as pharmaceutical product, anutritional product, an herbicidal product, or a pesticidal product. Theterm is intended to embrace substances whose function is as a carrier,diluent or bulking agent for the additive (for instance, in foodproducts, a polymer such as a cellulosic polymer may be coated with apleasant tasting additive such as a sugar, to yield a product having thedesired flavor but with a reduced additive concentration).

The active substance may be a single active substance or a mixture oftwo or more. It may be monomeric, oligomeric or polymeric, organic(including organometallic) or inorganic, hydrophilic, or hydrophobic. Itmay be a small molecule, for instance a synthetic drug like paracetamol,or a larger molecule such as a polypeptide, an enzyme, an antigen orother biological material. It is typically (although not necessarily)crystalline or semi-crystalline, preferably crystalline, by which ismeant that it is capable of existing in a crystalline form under thechosen operating conditions.

The active substance preferably comprises a pharmaceutically activesubstance, although many other active substances, whatever theirintended function (for instance, herbicides, pesticides, foodstuffs,nutraceuticals, dyes, perfumes, cosmetics, detergents, etc. . . . ), maybe coformulated with additives in accordance with the invention.

In particular the active substance may be a material (such as a drug)intended for consumption, which has an unpleasant taste and/or odor andneeds to be coated with a taste masking agent. Examples include, but arenot limited to, the bitter tasting anti-malarial drugs quinine sulphateand chloroquine; many oral corticosteroids such as are used for asthmatreatment; many antibiotics; Dicyclomine HCl (anti-spasmodic);dipyridamole (platelet inhibitor); Toprimate (anti-epileptic); Oxycodone(analgesic); Carispodol (used in the treatment of hyperactivity ofskeletal muscles); Bupropion (anti-depressant); Sumatripan (used inmigraine treatment); Verapamil HCl (calcium ion flux inhibitor);Tinidazole (anti-parasitic); acetyl salicylic acid (aspirin,anti-pyretic); Cimetidine HCl (used in the treatment of acid/pepticdisorders); Diltiazem HCl (anti-anginal); theophylline; paracetamol; andOrphenadrine citrate (anti-muscarinic). Clearly this list is notexhaustive.

The active substance may be a material which requires a protectivecoating because it is sensitive to heat, light, moisture, oxygen,chemical contaminants or other environmental influences, or because ofits incompatibility with other materials with which it has to be storedor processed.

Active substance instability can be a particularly acute problem in thecase of pharmaceuticals, since degradation can lead not only to areduction in the active substance concentration or its bioavailability,but also in cases to the generation of toxic products and/or to anundesirable change in physical form or appearance. The most commonreasons for degradation of drug substances exposed to atmosphericstresses are oxidation, hydrolysis and photochemical decomposition.

Actives susceptible to hydrolysis typically contain one or more of thefollowing functional groups: amides (e.g., as in dibucaine, benzylpenicillin, sodium chloramphenicol and ergometrine); esters (e.g., as inprocaine, tetracaine, methyladopate and physostigmine); lactams (e.g.,as in cephalosporin, nitrazepam and chlorodiazeproxide); lactones (e.g.,as in pilocarpine and spironolactone); oximes (e.g., as in steroidoximes); imides (e.g., as in glutethimide and ethosuximide); malonicurease (e.g., as in barbiturates); and nitrogen mustards (e.g., as inmelphalan).

Actives that undergo photochemical decomposition include hydrocortisone,prednisolone, some vitamins such as ascorbic acid (vitamin C),phenothiazine and folic acid. Those that can be affected by oxidativedegradation, often under ambient conditions, include morphine, dopamine,adrenaline, steroids, antibiotics and vitamins.

In some cases, however, it may be preferred for the active substance notto be ascorbic acid.

The additive may also be a single substance or a mixture of two or more,and may be monomeric, oligomeric or polymeric (typically eitheroligomeric or polymeric). It may be organic (including organometallic)or inorganic, hydrophilic or hydrophobic. It is typically a substancecapable of protecting an active substance from external effects such asheat, light, moisture, oxygen or chemical contaminants, and/or ofreducing incompatibilities between the active substance and anothermaterial with which it needs to be processed or stored, and/or ofdelaying, slowing or targeting the release of the active substance (forinstance, for drug delivery systems), and/or of masking the flavorand/or odor of an active substance, when applied to the surface of theactive substance. It is preferably non-toxic and pharmaceuticallyacceptable. In particular it may be a hydrophobic polymer such as anethyl cellulose.

The additive may in particular be a taste and/or odor masking agent, inwhich case it should be a flavor and odor-free, or at least a pleasanttasting and smelling material, preferably hydrophobic, which is notsignificantly degraded by saliva during the typical residence times of aconsumable product, such as a drug or foodstuff, in a consumer's mouth.Water insoluble polymers are particularly suitable as taste maskingagents.

Instead or in addition, the function of the additive may be to delayrelease of the active substance and/or to target its delivery to apredetermined site or reagent species. This is of particular use whenthe active substance is a pharmaceutical (for example, drug delivery canbe targeted to the intestines and colon using a coating which isinsoluble in gastric fluids), but may also be necessary for instance todelay the onset of a chemical reaction involving the active substance.

In some cases, the additive may itself be an “active” (e.g.,pharmaceutically active) substance, for instance where two or more drugsare to be co-administered but one must be released before another.

Examples of pharmaceutically acceptable additives include celluloses andcellulose derivatives (e.g., ethyl cellulose (hydrophobic coatingagent), hydroxyethyl cellulose (commonly used for tablet coatings),hydroxypropyl cellulose and hydroxypropyl methyl cellulose); polymersincorporating phthalate groups, such as hydroxypropyl methyl phthalate(used as an enteric coating for tablets and granules); acrylates andmethacrylates, such as the polymethyl acrylates and methacrylatesavailable as Eudragit™; polyoxyalkylenes, such as polyoxyethylene,polyoxypropylene and their copolymers which are available for instanceas Poloxamer™, Pluronic™ and Lutrol™; vinyl polymers such as polyvinylalcohol; homo- and co-polymers of hydroxy acids such as lactic andglycolic acids; and mixtures thereof. These are all amorphous or, in thecase of (co)polymers incorporating lactic acid, semi-crystalline.

Other commonly used coating additives include naturally occurring gumssuch as shellac, and many lipidic materials, examples being lecithin,waxes such as carnauba wax and microcrystalline wax, and phospholipidssuch as DPPC (dipalmitoyl phosphatidyl choline). The additive may be orcontain flavorings, including sugars and sweeteners. Again, these listsare by no means exhaustive.

Preferred additives are those which are amorphous or semi-crystalline,most preferably amorphous, in nature. Suitably the additive isoligomeric or polymeric; most preferably it is a polymeric material. Italso preferably has film forming capabilities, under the operatingconditions used; polymers known to have such capabilities include ethylcellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

It may in cases, in particular where the active substance is crystallineor semi-crystalline, be unsuitable for the additive to be polyvinylpyrrolidone (PVP), since this is known to inhibit crystallization andmay lead to a homogeneous, amorphous active/additive dispersion ratherthan a “coated”-type system.

In some cases it may be preferred for the additive not to be a cationicpolymer or copolymer, in particular not a cationic copolymer synthesizedfrom acrylates and/or methacrylates such as from dimethylaminoethylmethacrylate and neutral methacrylic acid esters.

In certain cases it may be preferred for the additive not to be a homo-or co-polymer of hydroxy acids such as lactic and glycolic acids, inparticular not to be poly(glycolic acid).

It may also be unsuitable, if the active substance is paracetamol,theophylline or ascorbic acid, in particular ascorbic acid, for theadditive to be a hydrophobic polymer, in particular ethyl cellulose. Ifthe active substance is ketoprofen, it may be unsuitable for theadditive to be hydroxypropyl methyl cellulose.

The active substance and/or the additive may be formed from an in situreaction (i.e., a reaction carried out immediately prior to, or on,contact with the anti-solvent fluid) between two or more reactantsubstances each carried by an appropriate vehicle.

The vehicle is a fluid capable of dissolving both the active substanceand the additive, the solubility of the active substance and theadditive in the vehicle being preferably 0.5-40% w/v, more preferably1-20% w/v or 1-10% w/v. In particular, the vehicle should form, with theactive and the additive, a single-phase solution rather than forinstance an emulsion or other form of colloidal dispersion.

The concentration of the additive in the target solution is suitably(particularly in the case of a polymeric additive) 10% w/v or less, moresuitably 5% w/v or less, such as between 1 and 2% w/v.

The vehicle must be miscible with the anti-solvent fluid under theoperating conditions used to carry out the SEDS™ process. (By “miscible”is meant that the two fluids are miscible in all proportions, and/orthat they can mix sufficiently well, under the operating conditionsused, as to achieve the same or a similar effect, i.e., dissolution ofthe fluids in one another and precipitation of the active substance andadditive.) The vehicle and anti-solvent are preferably totally misciblein all proportions, again under the operating conditions at the point ofvehicle/anti-solvent contact.

The term “vehicle” includes a single fluid or a mixture of two or morefluids, which are typically liquids but may be, for instance,supercritical or near-critical fluids. The fluids may be organicsolvents or aqueous. In the case of a vehicle comprising two or morefluids, the overall mixture should have the necessary solubility andmiscibility characteristics vis-à-vis the active substance, the additiveand the anti-solvent fluid.

The vehicle or its component fluids may contain, in solution orsuspension, other materials apart from the active substance andadditive.

The selection of ail appropriate vehicle depends on the activesubstance, the additive and the anti-solvent fluid as well as on thechosen operating conditions (including pressure, temperature and fluidflow rates). Based on the above guidelines as to the miscibility andsolubility characteristics of the fluids involved, the skilled personwould be well able to select suitable materials with which to carry outthe method of the invention.

When the vehicle is composed of two or more fluids, for instance anorganic solvent with a minor amount of a co-solvent “modifier”, or awater/organic solvent mixture, the two or more fluids may be mixed, soas to form the target solution, in situ, i.e., at or immediately beforethe target solution contacts the anti-solvent fluid and particleformation occurs. Thus, in one embodiment of the invention, the activesubstance is dissolved in a first fluid and the additive in a secondfluid, and the first and second fluids are mixed, so as to form thetarget solution, at or immediately before the target solution contactsthe anti-solvent fluid and precipitation occurs.

Ideally this mixing of the vehicle fluids occurs at the outlet of anozzle used to co-introduce the fluids into a particle formation vessel.For example, a first fluid in which the active substance is dissolvedmay be introduced through one passage of a multi-passage co nozzle asdescribed in WO-96/00610 (FIGS. 3 and 4) or WO-01/03821 (FIG. 4). Asecond fluid, in which the additive is dissolved, may be introducedthrough another passage of the nozzle. The nozzle passage outlets may bearranged to terminate adjacent one another at the entrance to theparticle formation vessel, in a way that allows the two fluids to meetand mix inside the nozzle, immediately before coming into contact withan anti-solvent fluid introduced through another nozzle passage. Bothfluids will be extracted together into the anti-solvent fluid, resultingin co-precipitation of the active substance and the additive. For thisto work, at least one of the vehicle fluids should be miscible, orsubstantially so, with the anti-solvent fluid. Ideally, although notnecessarily (as described in WO-01/03821), the two vehicle fluids shouldbe miscible or substantially miscible with one another.

Such in situ mixing of vehicle fluids may be particularly useful ifthere is no readily available common solvent for the active substanceand the additive (for instance, when one material is organic and theother inorganic), or if the active substance and additive solutions arein some way incompatible, for instance if the active and additive wouldform an unstable solution mixture in a common solvent.

The anti-solvent fluid is a fluid, or a mixture of fluids, in which boththe active substance and the additive are for all practical purposes (inparticular, under the chosen operating conditions and taking intoaccount any fluid modifiers present) insoluble or substantiallyinsoluble. By “insoluble” is meant that the anti-solvent cannot, at thepoint where it extracts the vehicle, extract or dissolve the activesubstance or additive as particles are formed. Preferably the activesubstance and the additive are less than 10⁻⁵ mole %, more preferablyless than 10⁻⁷ mole % or less than 10⁻⁸ mole %, soluble in theanti-solvent fluid.

The anti-solvent fluid should be a supercritical or near-critical fluidunder the operating conditions used. By “supercritical fluid” is meant afluid at or above its critical pressure (P_(c)) and critical temperature(T_(c)) simultaneously. In practice, the pressure of the fluid is likelyto be in the range (1.01-9.0)P_(c), preferably (1.01-7.0)P_(c), and itstemperature in the range (1.01-4.0)T_(c) (where T_(c) is measured inKelvin). However, some fluids (e.g., helium and neon) have particularlylow critical pressures and temperatures, and may need to be used underoperating conditions well in excess of (such as up to 200 times) thosecritical values.

The term “near-critical fluid” encompasses both high pressure liquids,which are fluids at or above their critical pressure but below (althoughpreferably close to) their critical temperature, and dense vapors, whichare fluids at or above their critical temperature but below (althoughpreferably close to) their critical pressure.

By way of example, a high pressure liquid might have a pressure betweenabout 1.01 and 9 times its P_(c), and a temperature between about 0.5and 0.99 times its T_(c) preferably between 0.8 and 0.99 times itsT_(c). A dense vapor might, correspondingly, have a pressure betweenabout 0.5 and 0.99 times its P_(c) (preferably between 0.8 and 0.99times), and a temperature between about 1.01 and 4 times its T_(c).

The anti-solvent is preferably a supercritical fluid such assupercritical carbon dioxide, nitrogen, nitrous oxide, sulfurhexafluoride, xenon, ethane, ethylene, chlorotrifluoromethane,chlorodifluoromethane, dichloromethane, trifluoromethane or a noble gassuch as helium or neon, or a supercritical mixture of any of these. Mostpreferably it is supercritical carbon dioxide, ideally on its own ratherthan in admixture with other fluids such as supercritical nitrogen.

When carrying out the embodiments of the invention using a supercriticalor near-critical fluid anti-solvent, the operating conditions mustgenerally be such that the solution which is formed when theanti-solvent extracts the vehicle remains in thesupercritical/near-critical form during the particle formation step.This supercritical/near-critical solution should therefore be above theT_(c) and P_(c) of the vehicle/anti-solvent mixture. This generallymeans that at least one of its constituent fluids (usually theanti-solvent fluid, which in general will be the major constituent ofthe mixture) should be in a supercritical or near-critical state at thetime of particle formation. There should at that time be a single-phasemixture of the vehicle and the anti-solvent fluid, otherwise theparticulate product might be distributed between two or more fluidphases, in some of which it might be able to re-dissolve. This is whythe anti-solvent fluid needs to be miscible or substantially misciblewith the vehicle.

The anti-solvent fluid may contain one or more modifiers, for examplewater, methanol, ethanol, isopropanol or acetone. A modifier (orco-solvent) may be described as a chemical which, when added to a fluidsuch as a supercritical or near-critical fluid, changes the intrinsicproperties of that fluid in or around its critical point, in particularits ability to dissolve other materials. When used, a modifierpreferably constitutes not more than 40 mole %, more preferably not morethan 20 mole %, and most preferably between 1 and 10 mole %, of theanti-solvent fluid.

The anti-solvent flow rate will generally be chosen to ensure an excessof the anti-solvent over the target solution when the fluids come intocontact, to minimize the risk of the vehicle re-dissolving and/oragglomerating the particles formed. At the point of its extraction thevehicle may typically constitute 80 mole % or less, preferably 50 mole %or less or 30 mole % or less, more preferably 20 mole % or less and mostpreferably 5 mole % or less, of the fluid mixture formed.

By “a SEDS™ particle formation process” is meant a process as describedin WO-95/01221, WO-96/00610, WO-98/36825, WO-99/44733, WO-99/59710,WO-01/03821 and/or WO-01/15664, in which a supercritical ornear-critical fluid anti-solvent is used simultaneously both todisperse, and to extract a fluid vehicle from, a solution or suspensionof a target substance. Such a technique can provide better, and moreconsistent, control over the physicochemical properties of the product(particle size and size distribution, particle morphology, etc. . . . )than has proved possible for coformulations in the past.

The simultaneous vehicle dispersion and extraction are preferablyachieved by co-introducing the fluids into a particle formation vesselin such a way that the anti-solvent and the target solution both enterthe vessel at the same point, which is substantially the same as thepoint where they meet and at which particle formation occurs. This issuitably achieved using a fluid inlet nozzle having two or more coaxial,concentric passages such as is shown in FIGS. 3 and 4 of WO-95/01221.

Because some embodiments of the invention are a modified version ofthose disclosed in the above listed patent publications, technicalfeatures of the processes described in those documents can apply also toembodiments of the invention. The earlier documents are thereforeintended to be read together with the current application.

The concentration of the active substance and the additive in the targetsolution must be chosen to give the desired active:additive ratio in thefinal product. In the case of a crystalline or semi-crystalline activesubstance, it is preferred that their relative concentrations be suchthat the active is able to precipitate in a crystalline form under theoperating conditions used (with some additives, in particular polymericexcipients, most particularly semi-crystalline and/or amorphouspolymers, too high an additive level can force the active to precipitatein an amorphous form homogeneously dispersed throughout a “matrix” ofthe additive, with no outer coating). At the same time, the relativeactive and additive concentrations when carrying out embodiments of theinvention are preferably such that there is sufficient additive togenerate an additive-rich, preferably active-free or substantially so,layer at the particle surface (too low an additive level could beinsufficient to achieve “coating” of all particles).

The additive level in the co-precipitated particles may be up to 50, 60,70 or even 80% w/w. However, particularly preferred are relatively lowlevels of the additive, for instance 45% w/w or less, preferably 40% w/wor less, more preferably 30% w/w or less, most preferably 25% or 20% or15% or 10% or 5% w/w or less. The active substance level is therefore,correspondingly, preferably 55% w/w or greater, more preferably 60% w/wor greater, most preferably 70% or 75% or 80% or 85% or 90% or 95% w/wor greater.

However, too low an additive concentration can be insufficient to form aprotective surface layer around the active-rich particle core. Theadditive level may therefore be preferred to be at least 1%, preferablyat least 2%, more preferably at least 5%, most preferably at least 10%or 20% w/w. For a taste masking additive, the level may be preferred tobe at least 10% w/w, preferably at least 15% w/w, more preferably atleast 20% or 25% or 30% or 40% w/w, of the overall composition. Theamount needed for effective coating will depend to an extent on the sizeof the particles to be formed-smaller particles will have a highersurface area and thus require correspondingly higher additive levels.

Thus, preferred additive concentrations might be between 1% and 45% w/w,more preferably between 5% and 45% w/w, most preferably between 10% and40% w/w or between 15% and 35% w/w.

An appropriate active:additive concentration ratio will usually manifestitself by a reduction in the crystallinity of acrystalline/semi-crystalline active substance, when coformulated inaccordance with the invention, compared to its pure form, although notreduction to a completely amorphous phase. The ratio is preferably suchthat in the product coformulation, a crystalline or semi-crystallineactive substance demonstrates between 20% and 95%, preferably between50% and 90%, more preferably between 60% and 90% crystallinity ascompared to the active starting material. This indicates a degree ofactive/additive interaction, but not a truly intimate solid dispersion.

It is thus possible to test for an appropriate active:additiveconcentration ratio, for a system containing a crystalline orsemi-crystalline active substance, by preparing a range of samples withdifferent ratios and identifying an upper limit in the additiveconcentration, above which the active crystallinity is too greatlydisturbed (for example, less than 10% crystallinity, or 100% amorphous).A sensible additive level, below this limit, can then be found byidentifying systems in which the active crystallinity is appreciablyreduced (e.g., by at least 10% or preferably 20%, possibly by up to 30%or 40% or 50%).

Analysis by scanning electron microscopy (SEM) may suitably be used toestablish the nature of the products tested; differential scanningcalorimetry (DSC) and/or X-ray diffraction (XRD) may be used toinvestigate degree of crystallinity, typically by comparing with datafrom the pure, completely crystalline active starting material and alsoits totally amorphous form. Confocal Raman microscopy (for instance,using a system such as the HoioLab™ Series 5000) may also be used toestablish whether a given product has the desired active/additivedistribution—this builds up a “sectional” view through a particle andcan reveal the nature and/or relative quantities of the substancespresent in the section scanned.

As well as the relative concentrations of the active substance and theadditive, other parameters may be varied if necessary in order toachieve a coformulation in accordance with embodiments of the invention.Such parameters include the temperature and pressure at the point ofparticle formation, the concentrations of the active and additive in thetarget solution, the nature of the vehicle and of the anti-solvent fluid(taking account of any modifiers present) and their flow rates uponcontact with one another.

It has not previously been recognized that a co-precipitation processperformed using SEDS™, whatever the relative concentrations of theco-precipitated species, could ever result in a product in which therewas both an intimate solid dispersion of the species and a coatingeffect of one species by the other, with no distinct phase boundarybetween the two regions.

The co-precipitated product of the method of the invention appears to bea type of solid dispersion, each particle containing a molecular-levelmixture of both the active substance and the additive. However, it hassurprisingly been found that the product is not a homogeneous mixture ofthe two components, but has a significantly lower level of the activesubstance at and near the surface of each particle compared to that inthe particle core, sufficient for the additive to form, in effect, aprotective surface layer. Thus, for example, a taste masking additivecan mask even a strongly flavored active substance, while at the sametime also being incorporated into the sub-surface core of each particle.There is typically, however, no distinct physical boundary between theprotective surface “layer” and the “enclosed” core, but instead agradual change, with a finite gradient, in the active:additive ratio.The particle constitution is that of a solid dispersion throughout, butwith a varying additive concentration across its radius.

It has also, surprisingly, been found that for certain active/additivesystems, in particular certain drug/polymer systems, SEDS™ coformulationdoes not readily yield an amorphous phase active, even up to in somecases 80% w/w additive. Instead the coformulated product can stillcontain crystalline active substance with a relatively high additiveconcentration at the particle surfaces.

The process of the invention works particularly well, it is believed(although we do not wish to be bound by this theory), when the activesubstance precipitates more quickly than the additive under theoperating conditions (including choice of solid and fluid reagents)used. More specifically, this occurs when the nucleation and/or particlegrowth rate of the active substance is higher, preferably significantlyhigher, than that of the additive. The quicker growing active substanceappears to precipitate initially as a “core” particle, around which boththe active and the additive collect as the solid particles grow, withthe relative concentration of the slower growing additive graduallyincreasing as the particles grow in diameter. Towards the outer surfacesof the particles, when most of the active present has alreadyprecipitated, the concentration of the additive becomes sufficientlyhigh that it then effectively “coats” the active-rich core.

Thus, the operating conditions and/or the reagents used in the method ofthe invention should ideally be chosen so as to enhance or maximize thedifference between the precipitation rates of the active substance andthe additive. (By “precipitation rate” is meant the combined effects ofthe nucleation and particle growth rates.) This may in turn meanenhancing or maximizing the chance of phase separation occurring,between on the one hand the active substance and its associated vehicleand on the other hand the additive and its associated vehicle,immediately prior to or at the point of particle formation; phaseseparation can inhibit formation of a truly homogeneous solid dispersionbetween the active and additive.

Certain active/additive pairs will already have significantly differentprecipitation rates. This appears particularly to be the case when theactive substance precipitates in a crystalline form and the additive inan amorphous form. Crystal habit may also affect the active substanceprecipitation rate. For example, it has been found that the inventedprocess can be effective for active substances having a needle-likecrystalline habit, possibly because the crystal growth rate issignificantly faster in one dimension than in the others. Generallyspeaking, the active substance may have a crystalline form (under theconditions used) which is significantly longer in one dimension than inat least one other dimension, and/or its crystals may grow significantlyfaster in one dimension than in at least one other dimension; thisembraces for example needle-like crystals and also, potentially, wafer-or plate-like crystals (for which growth is faster in two dimensionsthan in the third) and elongate prism-shaped crystals. Active substanceshaving other crystal habits, or amorphous actives, may of course beprotected using the method of the invention, using operating conditionssuitable to enhance the difference between the active and additiveprecipitation rates.

In the above discussion, “significantly” longer or faster meansapproximately 5% or more, preferably at least 10% or 20% or 30%, greaterthan the length or speed of the lower of the two parameters beingcompared.

Embodiments of the invention may also be effective when the activesubstance and the additive have significantly different (for instance,at least 5% different, preferably at least 10%, more preferably at least20% or 30%, based on the lower of the two values) solubilities in theanti-solvent fluid, as this can also affect the relative precipitationrates of the active and additive particles. This effect could beenhanced by the inclusion of suitable modifiers in the anti-solventfluid, and/or by introducing a “secondary” anti-solvent fluid, having alower capacity than the main anti-solvent for extracting the vehicle, asdescribed in WO-99/44733. Generally, the additive should be more solublethan the active substance in the anti-solvent fluid, which shouldpromote precipitation of the additive nearer to the particle surfaces.

Similarly, when the active substance and additive have a lowcompatibility with one another, i.e., a low solubility in or affinityfor or miscibility with one another, this too can make them less likelyto precipitate together in intimate admixture. For example, the activesubstance and additive will preferably have a solubility in one anotherof less than 30% w/w, more preferably less than 25% w/w, most preferablyless than 20% or 15% or 10% w/w.

Thus, the active substance and additive might preferably havesignificantly different polarities and thus low mutual solubilities anda low mutual affinity—this is likely to reduce interaction between theactive and additive during particle formation, and promote the growth ofactive-rich and additive-rich regions in the product particles.

Differences in polarity may be assessed for example by classifying eachreagent as either polar, apolar, or of intermediate polarity. Thepolarity of a substance is something which can be assessed by theaverage skilled person by reference to the number, position and polarityof functional groups present on the substance, and can be affected byfactors such as substituent chain lengths. Polar substances for instancetypically contain a significant proportion of polar functional groupssuch as amine, primary amides, hydroxyl, cyano, carboxylic acid,carboxylate, nitrile, sulfoxide, sulfonyl, thiol, halide, and carboxylicacid halide groups, and other ionizable groups. Substances of mediumpolarity may contain functional groups of medium polarity, such as forinstance esters, aldehydes, ketones, sulfides and secondary and tertiaryamides. Substances of low polarity typically contain no functionalgroups or only functional groups of an apolar nature, such as alkyl,alkenyl, alkynyl, aryl and ether groups. Thus ethyl cellulose, forexample, a polymer whose chain structure is dominated by alkyl groups,is considered to be non-polar, whereas the presence of a significantnumber of hydroxyl groups in hydroxypropyl methyl cellulose (HPMC)renders it a polar substance.

For polymers, polarity may also depend on the grade, for instance themolecular weight, degree of substitution, degree of cross-linking andany other co-monomers present.

Polar compounds include for instance acidic or basic compounds, ioniccompounds, including salts, and otherwise highly charged species, vinylpolymers such as poly vinyl alcohol (PVA), HPMC as mentioned above,hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene glycols,polyacrylates and polymethacrylates and polyoxyalkylenes. Lowpolarity/apolar compounds include for example steroids, ethyl celluloseand lipidic materials. Materials of intermediate polarity include thepolylactides and glycolides and mixtures thereof.

Assigning a value of 1, 2 or 3 to each reagent, 1 meaning low polarityor apolar, 3 meaning highly polar and 2 representing substances ofintermediate polarity, it is preferred when practicing embodiments ofthe invention that the active substance and the additive have differentpolarity values. More preferably, the active has a polarity of 1 and theadditive of 3, or vice versa.

It might previously have been expected that in such incompatibleactive/additive systems, a rapid solvent removal process such as SEDS™would result in products containing two distinct phases, the active andadditive precipitating separately from the fluid vehicle. Instead, ithas surprisingly been found that SEDS™ may be used to generate a producthaving a gradual active/additive concentration gradient across it.

Instead or in addition, the operating conditions during the method ofthe invention may be modified to enhance the difference between theactive and additive precipitation rates. Operating under relatively mildtemperatures and/or pressures (for instance, only just above thecritical temperature and/or pressure of the anti-solvent fluid (togetherwith any modifiers which are present in it) may be expected to enhanceany inherent differences in particle precipitation rates, by reducingthe vehicle extraction rate and maximizing the chance of phaseseparation between the active and additive components.

Typically, such “mild” conditions might correspond to between 1 and 1.1times the critical temperature T_(c) (in Kelvin) of the anti-solventfluid, preferably between 1 and 1.05 times T_(c) or between 1.01 and 1.1times T_(c), more preferably between 1.01 and 1.05 times T_(c) orbetween 1.01 and 1.03 times T_(c). The pressure may be between 1 and 1.5times the critical pressure P_(c), preferably between 1.05 and 1.4 timesP_(c), more preferably between 1.08 or 1.1 and 1.35 times P_(c). In theparticular case of a carbon dioxide anti-solvent (T_(c)=304 K; P_(c)=74bar), typical operating temperatures might be between 304 and 313 K, andoperating pressures between 80 and 100 or 120 bar.

“Mild” working conditions may suitably be such that the anti-solventfluid is in a supercritical form but more liquid-like than gas-like inits properties, i.e., its temperature is relatively close to (forinstance, between 1 and 1.3 times) its T_(c) (measured in Kelvin), butits pressure is significantly greater than (for instance, between 1.2and 1.6 times) its P_(c). Typically, for a supercritical carbon dioxideanti-solvent, the operating conditions are chosen so that the density ofthe anti-solvent fluid is between 0.4 and 0.8 g/cm³, more preferablybetween 0.6 and 0.8 g/cm³. Suitable operating conditions for a carbondioxide anti-solvent are therefore between 25 and 50° C. (298 and 323K), preferably between 32 and 40° C. (305 and 313 K), more preferablybetween 32 and 35° C. (305 and 308 K), and between 70 and 120 bar,preferably between 70 and 110 bar, more preferably between 70 and 100bar.

Most preferred, when practicing embodiments of the invention, is to usean incompatible active/additive pair, as described above, and to carryout the particle formation under mild conditions, also as describedabove.

It can thus be important, when practicing the invention, to use a SEDS™process but in doing so to seek to minimize the rate of vehicleextraction by the anti-solvent. This appears to make possible thegradual additive concentration gradient which is characteristic ofproducts according to the invention. It is indeed surprising that aprocess such as SEDS™, which is known to involve an extremely rapidsolvent removal, can nevertheless be used to coformulate reagents intoproducts having a non-homogeneous active/additive distribution.

The rate of solvent extraction may be reduced in the ways describedabove, for instance by working under relatively “mild” conditions withrespect to the critical temperature and pressure of the anti-solvent.Instead or in addition, the vehicle and the anti-solvent fluid may bechosen to have less than complete miscibility (i.e., to be immiscible inat least some relative proportions) under the chosen operatingconditions, for instance to be less than very or freely soluble (e.g.,as defined in the British Pharmacopoeia 1999, Volume 1, pages 11 and 21)in one another. For a carbon dioxide anti-solvent, suitable vehiclesmight include higher boiling solvents, such as with a boiling point ofat least 373 K, for instance higher (such as C₄-C₁₀) alcohols such asbutanol, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) andmixtures thereof. Other, lower boiling solvents such as lower alcohols(e.g., methanol, ethanol), ketones (e.g., acetone) and the like,including mixtures of such solvents, may also of course be used. Thevehicle may if appropriate contain minor (e.g., 10% v/v or less) amountsof other solvents (which may include water) to modify its solubilitycharacteristics.

A higher target solution flow rate, relative to that of the anti-solventfluid, can also help to increase solvent extraction times. Suitably thefluid flow rates are selected so as to achieve, at the point of targetsolution/anti-solvent contact, a vehicle:anti-solvent mole ratio ofbetween 5 and 20%, preferably between 5 and 10%. A suitable flow ratefor a supercritical CO₂ anti-solvent, for instance, may be 20 mL/min,and the target solution flow rate may then suitably be 1 mL/min orgreater.

Moreover, a target solution containing a semi-crystalline or inparticular an amorphous additive will typically have a relatively highviscosity. This too can help to impede solvent removal, again slowingthe particle formation process and allowing the active substance toprecipitate more rapidly than the additive.

As described above, the method of the invention may be practiced usingtwo separate vehicle fluids, one carrying the active substance and onecarrying the additive, which contact one another only at or immediatelybefore their point of contact with the anti-solvent fluid (i.e., thepoint of vehicle extraction and particle formation). If the two vehiclefluids have significantly different solubilities in the anti-solventfluid, this can cause a small degree of phase separation at the point ofparticle formation, the extent of which depends, inter alia, on the timeperiod between the vehicles mixing and their contact with theanti-solvent fluid (which in turn depends on the fluid flow rates andthe internal geometry of the fluid inlet used), and again can lead todifferences in precipitation rate between the active and the additive.

Generally speaking, any difference in the rate of vehicle extraction, bythe anti-solvent fluid, between the active substance containing solutionand that carrying the additive, is thought to be able to increase theeffectiveness of embodiments of the invention. The rate of vehicleextraction is in turn influenced by the molecular interactions betweeneach solute and its respective solvent, high levels of interaction beinglikely to slow solvent extraction and inhibit precipitation. Thus, inthis version of the invention, the solubility of the active substance inits vehicle fluid should be significantly (for instance, 5% or more,preferably at least 10% or 20% or 30%, based on the lower of the twosolubilities) different to the solubility of the additive in its vehiclefluid. The active substance should ideally be less soluble in (i.e.,form weaker interactions with) its (first) vehicle fluid than theadditive is in its (second) vehicle fluid, so that the additive ismarginally less ready to precipitate than the active.

Modifiers (co-solvents) in one or more of the vehicle fluid(s) and/orthe anti-solvent fluid may be chosen to enhance such effects; operatingpressures and temperatures, and even fluid flow rates, may alsoinfluence them.

The method of the invention preferably involves selecting the reagents(i.e., the active substance, the additive, the vehicle fluid(s), theanti-solvent fluid and any modifiers or co-solvents present) and theoperating conditions (such as temperature and pressure at the point ofparticle formation, fluid flow rates and concentrations of the activeand the additive in the vehicle), in order to increase the difference inparticle precipitation rates, under the conditions used, between theactive substance and the additive. Preferably the precipitation ratedifference is at least 5% of that of the slower precipitating materialmore preferably at least 10%, most preferably at least 20% or 30% or 40%or 50% or 75% or 90% or 100%.

It can be seen from the above that there are several potential ways inwhich the precipitation rate difference may be enhanced or maximized inaccordance with the invention.

The method of the invention can provide significant advantages overknown methods for coating an active substance with an additive. Becauseit involves particle formation by SEDS™ it is a one-step process, whichcan be carried out in a closed environment, shielded if necessary fromlight, oxygen and other contaminants, and it allows excellent controlover the physicochemical characteristics of the product (such asparticle size and size distribution, morphology, purity, yield andhandling properties), as described in the prior art on SEDS™. It is alsoextremely useful for formulating small particles, which can otherwise bedifficult to coat.

The coformulated particles made according to the invention differ fromconventional coated products; they are solid dispersions of one materialin another, but with a finite gradient in the relative concentration ofthe additive, which concentration increases radially outwards from thecore to the surface of each particle. The particles are thus (inparticular at their surfaces) not truly homogeneous mixtures of the twocomponents, such as one would expect from a prior art coformulationprocess, since such mixtures would include at least some exposed activesubstance at the particle surfaces and hence be unsuitable forprotecting or masking the active substance. In particles made accordingto embodiments of the invention, the active substance:additive ratio, atthe particle surface, can be sufficiently low for a taste maskingadditive to mask, effectively, the flavor of for example an extremelybitter tasting drug such as quinine sulphate.

Nor, however, are the particles “coated”, in the conventional sense ofthe word, with the additive. They tend not to possess a core and aseparate coating layer with a distinct physical boundary (at whichboundary the “gradient” in the additive concentration is theoreticallyinfinite) between them. Rather, they exhibit a gradual change from anactive-rich core to an additive-rich (and preferably active-free)surface.

It is possible that the active substance at the core of a particleaccording to the invention will interact to at least some degree withthe additive present in the particle, and towards the centre theparticle may have the form of a solid dispersion of the active andadditive, manifested in general by a disturbance in the crystallinity ofa crystalline or semi-crystalline active even at the particle core.However it is also possible that a particle may be formed in which, atits centre, the active exists in a pure (and if relevant, crystalline)form. Evidence to date (in particular Raman confocal microscopy studies)suggest that a particle made by the method of the invention does notexhibit more than one separate “phase” nor any distinct phase boundary,but rather contains only gradual transitions between regions ofdifferent active:additive concentration ratios across its diameter.

Such particle properties, thought to be unique, are likely to influencetheir dissolution profiles, in particular where the additive acts toinhibit release of the active substance. The release-inhibiting effectis likely to be most marked during an initial period of timecorresponding to dissolution of the additive at the particle surfaces,and to falloff gradually thereafter.

Differential scanning calorimetry (DSC) data from the products is alsolikely to be affected by their unique active:additive concentrationprofile. For instance, when the active substance is crystalline orsemi-crystalline, it is expected that the DSC profile for a product madeaccording to the invention will exhibit one or more peaks indicative ofcrystalline active, but that the peak(s) will be broader to at leastsome degree than those for the pure active substance, indicating adegree of interaction between the active and the additive. When both theactive and the additive are crystalline or semi-crystalline, it can beexpected that the DSC profile of the coformulation will exhibit twodistinct peaks or sets of peaks, one for the active substance and onefor the additive, with both peaks/sets being broader than those for thepure starting materials, again indicating a degree of solid/solidinteraction but retention of at least some of the character of theindividual materials.

Similarly, X-ray diffraction (XRD) analysis of a product made accordingto the invention is likely to indicate reduced crystallinity for anormally crystalline active substance, due to interaction with theadditive, but not a completely amorphous system such as might be seenwith a truly homogenous solid dispersion.

The gradient in the relative additive concentration, across the particleradius, will depend on a number of factors such as the solubilitycharacteristics of the species present, the viscosities of theirsolutions, the nature and rate of their particle growth, etc., asdescribed above. The gradient mayor may not be constant across theradius, but the rate of change in additive concentration is typicallycontinuous rather than stepped, from the core to the additive-richsurface (which preferably contains, at its outer limit, 100% additive).It may be possible to identify “core” and “surface” regions of theparticles with a concentration gradient between them. In this case theconstitution of the “core” is preferably between 90 and 100% w/w activesubstance, more preferably between 95 and 100%, most preferably between98 and 100% w/w (it is possible that the core will contain no additiveat all).

The active substance in the core is preferably in a crystalline form,for instance between 80% and 100% or between 90 and 100%, ideally 100%crystalline.

The “surface” layer preferably contains between 5 and 0%, morepreferably between 2 and 0% or between 1 and 0% or between 0.5 and 0%,most preferably 0% w/w of the active substance, i.e., there ispreferably no active substance exposed at the outer particle surface.

For these purposes, the “surface” layer may suitably be taken to be theoutermost region containing 0.0001% or more of the total particlevolume, preferably 0.001% or more. The “core” region may suitably betaken to be the central region containing 0.0001% or more of the totalparticle volume, more preferably 0.001% or more. Either region may betaken to contain up to 0.01%, 0.1%, 1%, 5%, 10% or even 15% of the totalparticle volume.

The active:additive concentration gradient can be controlled, in themethod of the invention, by altering the operating conditions asdescribed above. It will be affected by these and by the nature of inparticular the active substance and the additive but also the vehicleand the anti-solvent fluid. The skilled person, using available data onthe solubilities, miscibilities and viscosities of the reagents he uses,should be well able to select and alter the operating conditions toinfluence the distribution of the additive in the product particles.

The degree of crystallinity of a normally crystalline active substancewill also vary gradually from the core to the surface of the particle.At the centre, the active substance may be highly, possibly even 100%,crystalline, but towards the surface its interaction with the additivewill typically be such as to disrupt its crystallinity and increasinglyhigh levels of amorphous phase active substance may be present as theparticle surface is approached. It can often be desirable, in forinstance drug/excipient formulations, for an active substance to bepresent in a more readily dissolvable (and hence more bioavailable)amorphous form; this characteristic of the products of the invention canthus be advantageous, particularly when combined with the coating effectwhich can mask unpleasant flavors and/or delay release of the activesubstance for a desired period of time.

According to a second aspect of embodiments of the invention, there isprovided a particulate coformulation of an active substance and a(typically protective) additive, of the type described above. Thecoformulation is a solid dispersion of one component in the other butwith a finite gradient in the relative additive concentration whichincreases radially outwards from the core to the surface of theparticles, the particles having an additive-rich surface region butpreferably no distinct physical boundary between that region and therest of the particle.

A particulate coformulation in accordance with the invention mayalternatively be described as an intimate, molecular level, solid-phasemixture of an active substance and an additive, the particles of whichhave an additive-rich, preferably active substance-free, surface region.The active substance:additive ratio, at the particle surface, ispreferably sufficiently low for the additive to form, effectively, aprotective surface layer around the active substance.

In the case where the active substance has an unpleasant flavor or odorand the additive is a taste masking agent, the active substance:additiveweight ratio, at the particle surfaces, is preferably sufficiently lowfor the additive to mask, effectively, the flavor or odor of the activesubstance.

The outer additive layer is preferably sufficient to prevent anydetectable release of the active substance for at least 30 seconds,preferably at least 60, more preferably at least 90 or 120 or 150 or 180or even 240 or 300 seconds after the product of the invention comes intocontact with saliva in a consumer's mouth (or on immersion of theproduct in a pH neutral aqueous solution). It may also be preferred forthere to be no detectable release of the active substance for at least2, more preferably 3 or even 4 or 5, minutes on immersion of the productin an aqueous solution of pH between 1 and 2, mimicking the conditionsin a consumer's stomach.

The thickness of the outer additive (“coating”) layer will depend on thenature of the active and additive, the size of the particle as a wholeand the use for which it is intended. Suitable outer layers might bebetween 0.1 and 10 μm in depth, more preferably between 0.1 and 5 μm.

A coformulation according to the invention preferably consistsessentially of the active substance and the additive, i.e., itpreferably contains no, or only minor amounts (for instance, less than5% w/w, preferably less than 2% w/w or less than 1% w/w) of, additionalingredients such as surfactants, emulsifiers and stabilizers. Itpreferably contains no bulking agents such as silica, in particularcolloidal silica.

A coformulation according to the second aspect of the invention ispreferably made by a method according to the first aspect. Aspects ofthe coformulation such as the nature, amounts and distribution of theactive substance and the additive are therefore preferably as describedabove in connection with the first aspect of the invention. Thecoformulation may in particular be or comprise a pharmaceutical ornutraceutical agent or a foodstuff. The active substance is preferablypresent in a crystalline form and the additive in an amorphous form.

The coformulation may have a particle volume mean diameter (in the caseof spherical or approximately spherical particles) of between 0.5 and100 μm, preferably between 0.5 and 20 μm, more preferably between 0.5and 10 μm or between 1 and 10 μm. In the case of needle-like particles,the volume mean particle length is typically between 5 and 100 μm,preferably between 10 and 100 μm, more preferably between 50 and 100 μm,and the volume mean thickness between 0.5 and 5 μm, preferably between 1and 5 μm. In the case of plate-like particles, the volume mean thicknessis typically between 0.5 and 5 μm. Embodiments of the invention can thusbe of particular benefit in preparing small particles having aneffective coating deposited on them, since using conventional coatingtechnologies the coating of fine particles (for instance, of size below10 μm or 5 μm or more particularly below 1 μm) can be extremelydifficult. Embodiments of the invention allow both core and coating tobe generated in a single processing step, with a high level of controlover product characteristics such as size and size distribution.

A third aspect of an embodiment of the invention provides apharmaceutical composition which includes a coformulation according tothe second aspect. The composition may be, for example, a tablet orpowder, a suspension or any other dosage form, in particular oneintended for oral or nasal delivery.

A fourth aspect of the invention provides a foodstuff or nutraceuticalcomposition which includes a coformulation according to the secondaspect.

A fifth aspect provides the use of a SEDS™ co-precipitation process inpreparing particles of an active substance having a layer of an additiveon the particle surfaces. By “co-precipitation process” is meant amethod which involves dissolving both the active substance and theadditive in a vehicle to form a single target solution, and contactingthe target solution with an anti-solvent fluid so as to cause the activesubstance and additive to co-precipitate.

According to this fifth aspect of the invention, the SEDS™co-precipitation is used to achieve a coating of the additive at theparticle surfaces. Preferably the coating is a protective layer, inparticular a taste and/or odor masking layer. A SEDS™ co-precipitation(i.e., both active and additive being precipitated together from acommon solvent system) has not previously been used for such a purpose.

Some embodiments of the invention will now be described, by way ofexample only, with reference to the accompanying illustrative drawings,of which:

Experimental Examples A

These examples demonstrate the coformulation, using SEDS™, of the highlypolar anti-malarial drug quinine sulphate (QS) (Sigma™, UK) with theapolar polymer ethyl cellulose (EC-N7, Hercules™, UK). QS has anunpleasant bitter taste and would conventionally need to be coated witha taste masking agent prior to administration.

A SEDS™ process was used to precipitate both drug and polymer togetherfrom a single “target solution”. The apparatus used was analogous tothat described in WO-95101221 (FIG. 1), using a 50 mL Keystone™ pressurevessel (available from Keystone Scientific, Inc., located in Bellefonte,Pa.) as the particle formation vessel and a two-passage concentricnozzle of the form depicted in FIG. 3 of WO-95/01221. The nozzle outlethad an internal diameter of 0.2 mm. Supercritical carbon dioxide was thechosen anti-solvent. The particle formation vessel was maintained at 100bar and 35° C.

Example A1—Precipitation of QS Alone

A 1% w/v solution of QS in absolute ethanol was introduced into theparticle formation vessel at 0.3 mL/min through the inner nozzlepassage. Supercritical carbon dioxide was introduced at 9 mL/min throughthe outer nozzle passage. Particles formed and were collected in thevessel.

The product was a fine, fluffy white powder. SEM (scanning electronmicroscope) examination showed a needle-like morphology (FIG. 1),different to that of the starting material (FIG. 2).

Example A2—Co-Precipitation of QS and Ethyl Cellulose

A 1% w/v solution of QS in absolute ethanol, also containing 20% byweight (based on the overall drug/polymer mix) of ethyl cellulose, wasintroduced into the particle formation vessel with supercritical carbondioxide, using the same operating temperature and pressure, and the samefluid flow rates, as for Example A1.

The product, collected in the vessel, was again a fine, fluffy whitepowder, having a similar particle morphology to the product of ExampleA1 (see the SEM photograph in FIG. 3).

Examples A3-A10—Increasing the Polymer Concentration

Example A2 was repeated but using 5%, 10%, 30%, 40%, 50%, 60%, 70% and80% w/w respectively of the ethyl cellulose polymer.

All products were fine, fluffy white powders. Those of Examples A3-A7(respectively 5%, 10%, 30%, 40% and 50% w/w ethyl cellulose) had aneedle-like particle morphology with smooth surfaces—see therepresentative SEM photographs in FIGS. 4, 5 and 6 for the products ofExamples A3, A4 and A6 respectively.

The Example A8 product (60% w/w ethyl cellulose) contained sphericalparticles, most likely of ethyl cellulose, deposited on the edges ofneedle-like particles (see FIG. 7). This effect became more marked asthe ethyl cellulose content increased, the spherical polymer particlescovering almost all the QS crystal surfaces in the products of ExamplesA9 (70% w/w ethyl cellulose, FIG. 8) and A10 (80% w/w ethyl cellulose,FIG. 9).

Results and Discussion

The X-ray diffraction (XRD) patterns for the products of Examples A2 toA10 were essentially similar (in terms of peak positions) to that of thepure, unprocessed QS powder (FIG. 10). This indicates that there hadbeen no solid state phase (polymorphic) change in the QS during SEDS™processing and that its crystalline phase was still present in allproducts. In other words, the products were not true solid “dispersions”of the drug in the polymer (as were, for example, the products describedin WO-01/15664). FIGS. 11 and 12 show the XRD patterns for the productsof Examples A6 and A8 respectively; a slight reduction in crystallinitycan be observed, which is consistent with the presence of the polymer inthe surface regions of the particles.

The XRD data are also consistent with the SEM observations ofcrystalline particles with polymer-like features on the particlesurfaces.

When co-formulating a drug with more than about 40% w/w of a polymer, ingeneral an amorphous particulate product would be expected. Typically,even at levels below 40% w/w, the presence of the polymer would still beexpected to cause a substantial decrease in the degree of drugcrystallinity. This is illustrated and confirmed by the teachings inWO-01/15664. It is therefore surprising to find that the products of thepresent examples retained a substantial degree of crystallinity, even inthose containing as much as 60% w/w (FIGS. 7 and 12) or 80% w/w (FIG. 9)of the polymer. It is thought that this could be due to the differencein the rate of solvent extraction, by the supercritical carbon dioxide,from the solution elements of on the one hand the drug and on the otherthe polymer, under the relatively mild working conditions used.Relatively high levels of interaction between the polymer and theethanol solvent, as compared to those between the QS and the ethanol,combined with relatively low levels of interaction between the polardrug and the hydrophobic polymer, could cause slower solvent extractionin the region of the polymer molecules, and hence delay or discouragetheir precipitation.

On tasting the products of Examples A5 to A10 (by four panelists), nobitterness could be detected for up to as long as 120 seconds or more.In contrast, pure QS gave an immediately detectable bitter taste. Thisindicates that, at least at the particle surfaces in the coformulatedproducts, there was no available QS and an extremely high (perhaps 100%)concentration of ethyl cellulose. That this can be achieved even at upto 70% w/w QS (Example A5) could be of significant benefit in theformulation of quinine sulphate dosage forms.

These tasting experiments, although not rigorous, provide an effectiveindication of the existence of a continuous protective layer, analogousto a coating, at the particle surfaces, an unexpected result from acoformulation process. It appears that this continuous layer is presentin addition to the separate particles of excess polymer which arevisible on the crystal surfaces in the Example A8 to A10 products (FIGS.7 to 9).

Experimental Examples B

These examples demonstrate the coformulation, using SEDS™, of theartificial sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester,Aldrich™, UK) with ethyl cellulose (EC-N7, Hercules™, UK). Aspartame isan intensely sweet chemical, having a sweetening power of approximately180 to 200 times that of sucrose, which is widely used in beverages,table-top sweeteners and other food and nutraceutical (for instance,vitamin preparations) products. It was chosen for these experimentsbecause of the ease with which it can be detected if insufficientlytaste masked.

The aspartame (polar) and ethyl cellulose (non-polar) were precipitatedtogether from a single “target solution” in a 1:1 v/v acetone:methanolsolvent mixture. The apparatus and operating conditions (temperature,pressure and fluid flow rates) used were the same as those in ExamplesA. Again the anti-solvent was supercritical carbon dioxide.

Example B1—Co-Precipitation of Aspartame and Ethyl Cellulose

The target solution contained 1% w/v aspartame and 10% w/w ethylcellulose. The product collected in the particle formation vessel was afine, fluffy white powder. SEM examination showed a needle-likemorphology (FIG. 14), similar to that of the aspartame starting material(FIG. 13), but with small spherical polymer particles visible on theaspartame crystal surfaces even at this relatively low polymerconcentration.

Examples B2 and B3—Increasing the Polymer Concentration

Example B1 was repeated but with ethyl cellulose concentrations of 30and 60% w/w respectively in the target solution. In both cases theproduct was a fine, fluffy white powder with similar morphology to thatof Example B1, although at these levels the polymer particles appearedcompletely to cover the aspartame crystals. FIG. 15 is an SEM photographof the Example B2 product (30% w/w ethyl cellulose); FIG. 16 shows thatof Example B3 (60% w/w ethyl cellulose).

The Example B2 product (30% w/w ethyl cellulose) was tasted by sevenpanelists. No sweetness was detected for more than 600 seconds. Incontrast, sweetness could be detected immediately from the as-suppliedaspartame starting material. The taste masking effect is believed to bedue to the hydrophobic ethyl cellulose layer covering virtually everyaspartame particle (FIG. 15).

Experimental Examples C

In these experiments, the method of the invention was used to apply ataste masking coating to a highly polar active substance (NaCl)precipitated from an aqueous solution. Two alternative processingmethods were used (Experiments C1 and C2). The products of bothexperiments were tasted by five panelists. Very little if any saltinesswas detected for more than 300 seconds, indicating efficient coating ofthe NaCl with the taste masking additive.

These results illustrate further the broad applicability of embodimentsof the invention.

Example C1—In Situ Mixing of Active and Additive Solutions

A three-passage coaxial nozzle, of the type illustrated in FIG. 3 ofWO-96/00610, was used to co-introduce into a 50 mL Keystone™ pressurevessel (a) a 30% w/v solution of pure NaCl (>99%, Sigma™ UK) indeionized water, (b) a 0.22% w/v solution of EC-N7 (as in Examples B) inpure methanol and (c) supercritical carbon dioxide as the anti-solvent.The NaCl and EC-N7 solutions, introduced through the intermediate andinner nozzle passages respectively, met inside the nozzle immediatelyprior to their contact with carbon dioxide flowing through the outernozzle passage.

The flow rates for the fluids were (a) 0.02 mL/min, (b) 1.2 mL/min and(c) 36 mL/min. The pressure vessel was maintained at 100 bar and 35° C.The nozzle outlet had an internal diameter of 0.2 mm.

The relative NaCl and EC-N7 concentrations yielded a coformulationcontaining 30% w/w of the ethyl cellulose. The product was a fine,fluffy, white powder; SEM analysis showed microparticles with a roundedmorphology (FIG. 18) which were much smaller than those of the asreceived, milled pure NaCl (FIG. 17).

FIGS. 20 and 21 are XRD patterns for the NaCl starting material and theExample C1 product respectively. That for the C1 product indicates aslight reduction in crystallinity compared to that for the startingmaterial, due to the presence of the polymer.

Example C2—Pre-Mixing of Active and Additive Solutions

In this experiment, 0.3 g of pure NaCl was dissolved in 1 mL ofdeionized water to form solution A, 0.13 g of EC-N7 was dissolved in 60mL of pure methanol to form solution B. Solution B was then added tosolution A to form a solution mixture C. Mixture C was then pumped at0.3 mL/min into a 50 mL Keystone™ vessel kept at 100 bar and 35° C., viathe inner passage of a two-passage coaxial nozzle (outlet diameter 0.2mm) as used in Examples B. Supercritical carbon dioxide was introducedat 9 mL/min through the outer nozzle passage.

The product was a fine, fluffy white powder (SEM photomicrograph shownin FIG. 19) having a similar morphology to that of the Example C1product.

Experimental Example D—Product Characterization

In this example, the constitution of a product prepared according to theinvention was analyzed.

The product contained 20% w/w quinine sulphate (QS) with an ethylcellulose (EC) coating agent. It was prepared in the same way asExamples A, using the same operating temperature, pressure and fluidflow rates and the same two-passage coaxial nozzle. Supercritical carbondioxide was the anti-solvent and the drug and coating agent weredissolved in absolute ethanol at 1% w/v.

The product was analyzed by Raman spectroscopy using the Kaiser™ Ramanconfocal microscope system (HoloLab™ Series 5000). This builds up across-sectional image of the constitution of the product particles. Thelaser power at the sample was approximately 27 mW at 785 nm from anattenuated Kaiser™ Invictus™ diode laser.

FIG. 22A shows a visual image of the sample, in which the needle-like QScrystals are visible. The two crosses indicate the Raman mapping area,which was 15×18 μm. FIG. 22B is a contour map based on integration ofthe signal from the band at 1370 cm⁻¹ that corresponds to the vibrationof quinine. This band is not present in the spectrum of the pure ECpolymer; its absence is indicated by the darkest shaded outer regions inFIG. 22B. The white areas represent pure QS.

FIG. 22B shows clearly that the product particles contain outer regionsof pure EC and are thus completely “coated”. Some also contain a QS“core” from which the EC protectant is completely absent. Other shadedareas in FIG. 22B reflect the intensity scale gradient of the 1370 cm⁻¹spectral band and therefore indicate different drug:polymer ratios.These contours indicate not the existence of different compounds ordiscrete phases but a gradual change in the QS:EC concentration ratiobetween the core and the surface of the particle.

Experimental Examples E

These examples investigated the residual solvent content and stabilityof ethyl cellulose (EC)-coated quinine sulphate (QS) prepared accordingto embodiments of the invention.

The product of Example A7 (50% w/w QS in EC) was analyzed for residualsolvent (ethanol) content using the head space gas chromatography method(Genesis™ Headspace Analyzer fitted on the Varian™ 3400 Serieschromatograph).

The analysis showed a residual ethanol content of less than 500 ppm,which represents the lower quantifiable limit. This is also much lowerthan the limit specified in the ICH (International Conference onHarmonization of Technical Requirements for Registration ofPharmaceuticals for Human Use) guidelines, which is currently 5000 ppmfor ethanol.

For the assessment of stability, 200 mg of the Example A6 product (60%w/w QS in EC) was stored for a month at room temperature and 100%relative humidity, alongside a sample of the as-received pure QS. Thesample prepared according to embodiments of the invention showed nochange in powder physical appearance or flow properties after storage.In contrast the uncoated QS showed signs of partial caking and a lowerdegree of powder flowability. This indicates that the invented producthad an effective polymer coating, adequate to protect the encapsulatedactive from environmental humidity and enhance its storage stability.

While the foregoing is directed to embodiments of the invention, otherand further embodiments of the invention may be devised withoutdeparting from the basic scope thereof, and the scope thereof isdetermined by the claims that follow.

1. A method of preparing a particulate co-formulation, the methodcomprising: (i) dissolving an active substance and an additive in avehicle to form a single phase target solution; (ii) co-introducing intoa particle formation vessel, (a) a supercritical fluid that is misciblein all proportions with the vehicle and in which the active substanceand the additive are insoluble or substantially insoluble, and (b) thetarget solution, such that the supercritical fluid and target solutionenter the vessel at the same point and under conditions effective todisperse the target solution in the supercritical fluid and extract thevehicle therefrom, to thereby form a co-precipitated particulate productthat is a solid dispersion of the active substance and the additive,wherein the particles of the particulate product have a finite gradientin relative additive concentration that increases radially outwards fromthe core to the surface of the particles, such that the particlescomprise an additive-rich surface region but do not possess separatecore and coating layers with a distinct physical boundary between them.2. The method of claim 1, wherein the active substance is selected fromthe group consisting of pharmaceutically active substances, herbicides,pesticides, foodstuffs, and a nutraceuticals.
 3. The method of claim 2,wherein the active substance is a pharmaceutically active substance. 4.The method of claim 1, wherein the active substance is crystalline. 5.The method of claim 1, wherein the additive is an oligomer or a polymer.6. The method of claim 5, wherein the additive is a hydrophobic polymer.7. The method of claim 5, wherein the additive is selected fromcelluloses, phthalates, acrylates, methacrylates, polyoxyalkylenes andtheir copolymers, vinyl polymers, homo- and co-polymers of hydroxyacids, and mixtures of the foregoing.
 8. The method of claim 1, wherethe solubility of the active substance and the additive in the vehicleare each in a range of about 0.5-40% w/v.
 9. The method of claim 1,wherein the concentration of the additive in the target solution is 10%w/v or less.
 10. The method of claim 1, where the supercritical fluid isselected from supercritical carbon dioxide, nitrogen, nitrous oxide,sulfur hexafluoride, xenon, ethane, ethylene, chlorotrifluoromethane,chlorodifluoromethane, dichloromethane, trifluoromethane, helium, neon,or a supercritical mixture of any of the foregoing.
 11. The method ofclaim 10, wherein the supercritical fluid is supercritical carbondioxide.
 12. The method of claim 1, wherein the supercritical fluidoptionally comprises a co-solvent.
 13. The method of claim 1, whereinthe supercritical fluid and the target solution are co-introduced via afluid inlet nozzle having two or more coaxial, concentric passages. 14.The method of claim 11, wherein the conditions in step (b) comprise atemperature between 25 and 50° C. (298 and 323 K) and a pressure between70 and 120 bar.
 15. The method of claim 1, wherein the relativeconcentration of the additive in the particles of the particulateproduct is up to about 60% by weight.
 16. The method of claim 1, whereinthe surface of the particles of the particulate product is free ofactive substance.
 17. The method of claim 1, wherein the surface of theparticles of the particulate product has a concentration of about 5% orless by weight of the active substance.
 18. The method of claim 1,wherein the particles of the particulate product are spherical orapproximately spherical particles having a volume mean diameter of lessthan 100 μm, or needle-like particles having a volume mean length withina range from about 5 μm to about 100 μm and a volume mean thicknesswithin a range from about 0.5 μm to about 5 μm, or plate-like particleshaving a volume mean thickness within a range from about 0.5 μm to about5 μm.
 19. The method of claim 18, wherein the particles of theparticulate product are spherical or approximately spherical particleshaving a volume mean diameter within a range from about 0.5 μm to about20 μm.
 20. The method of claim 19, wherein the particles of theparticulate product have a volume mean diameter within a range fromabout 0.5 μm to about 10 μm.